The mammalian bombesin (Bn)-related peptides, gastrin-releasing peptide (GRP) and neuromedin B (NMB) have a wide range of biological and pharmacological effects. These include stimulation of the release of numerous gastrointestinal hormones and peptides, stimulation of exocrine gland secretion chemotaxis, contraction of smooth muscle, effects in the central nervous system such as thermoregulabon, behavioral effects, maintenance of circadian rhythm, inhibition of TSH release and safety. Bn-related peptides also function as a growth factor in numerous normal cells (e.g., bronchial cells, endometrial stomal cells and 3T3 cells) as well as neoplastic cells such as human small cell lung cancer cells, rat hepatocellular tumor cells, prostatic cells and breast adenocarcinoma cells.
Recent structure-function and cloning studies demonstrate that at least two classes of receptors mediate the actions of Bn-related peptides. One class, the GRP-preferring subtype (GRP receptor or GRP-R), has a high affinity for GRP and low affinity for NMB, whereas the other class, the NMB-preferring subtype (NMB receptor or NMB-R), has a high affinity for NMB and lower affinity for GRP. Both classes of receptors are widely present both in the central nervous system and in the gastrointestinal tract. Until recently, the physiological importance of Bn-related peptides in mediating various processes or which receptor subtype mediated the various reported biological effects of Bn-related peptides was unclear.
Five different classes of Bn-receptor antagonists have been described. Jensen, R. T. et al. Trends Pharmacol. Sci. 12:13 (1991). Members of a number of these classes have high potency, long duration of action and selectivity for the GRP receptor and thus are useful even in vivo for defining the role of GRP or GRP receptors in mediating various physiological events. However, at present few antagonists for the NMB receptor which are sufficiently selective or potent have been described. (See, e.g., Coy, D., and Taylor, J., U.S. Pat. No. 5,462,926.) Further, NMB has been implicated in the inhibition of lung cancer and gliomas, Cancer Res 1991 Oct. 1 51:19 5205-11; J Cell Biochem Suppl 1996 24: 237-46, Peptides 1995 16:6 1133-40; J Pharmacol Exp Ther 1992 October 263:1 311-7), stimulation of appetite, (Eur J Pharmacol 1994 Dec. 12 271:1 R7-9; Am J Physiol 1997 January 272:1 Pt 2 R433-7; Pharmacol Biochem Behav 1996 August 54:4 705-11), stimulation of TSH secretion, (hypothyroidism), (Regul Pept 1996 Nov. 14 67:1 47-53), and inhibition of aldosterone secretion, (hyperaldosteronism), (Histol Histopathol 1996 October 11:4 895-7). Thus, the compounds of the present invention are useful in the investigation of the physiological role played by NMB, and in the development of therapeutic compositions for treatment of NMB-related indications.
As is known in the art, agonists and antagonists of somatostatin are useful for treating a variety of medical conditions and diseases, such as inhibition of H. pylori proliferation, acromegaly, restenosis, Crohn's disease, systemic sclerosis, external and internal pancreatic pseudocysts and ascites, ViPoma, nesidoblastosis, hyperinsulinism, gastrinoma, Zollinger-Ellison Syndrome, diarrhea, AIDS related diarrhea, chemotherapy related diarrhea, scleroderma, Irritable Bowel Syndrome, pancreatitis, small bowel obstruction, gastroesophageal reflux, duodenogastric reflux and in treating endocrinological diseases and/or conditions, such as Cushing's Syndrome, gonadotropinoma, hyperparathyroidism, Graves' Disease, diabetic neuropathy, Paget's disease, and polycystic ovary disease; in treating various types of cancer such as thyroid cancer, hepatome, leukemia, meningioma and conditions associated with cancer such as cancer cachexia; in the treatment of such conditions as hypotension such as orthostatic hypotension and postprandial hypotension and panic attacks; GH secreting adenomas (Acromegaly) and TSH secreting adenomas. Activation of type 2 but not type 5 subtype receptor has been associated with treating prolactin secreting adenomas. Other indications associated with activation of the somatostatin subtypes are inhibition of insulin and/or glucagon and more particularly diabetes mellitus, hyperlipidemia, insulin insensitivity, Syndrome X, angiopathy, proliferative retinopathy, dawn phenomenon and Nephropathy; inhibition of gastric acid secretion and more particularly peptic ulcers, enterocutaneous and pancreaticocutaneous fistula, Dumping syndrome, watery diarrhea syndrome, acute or chronic pancreatitis and gastrointestinal hormone secreting tumors: inhibition of angiogenesis, treatment of inflammatory disorders such as arthritis; chronic allograft rejection; angioplasty; preventing graft vessel and gastrointestinal bleeding. Somatostatin agonists can also be used for decreasing body weight in a patient. Accordingly, the compounds of the instant invention are useful for the foregoing methods.
Recently, it was reported that a native somatostatin (SS), somatostatin-14 (SS-14), inhibited the cross-linking of 125I-GRP to a 120 kD protein in triton extracts of 3T3 cells and human small cell lung cancer cells which are known to possess bombesin receptors. Recent studies have also demonstrated SS-14 could also weakly inhibit binding to opiate receptors, and subsequent structure-function led to the identification of various D-amino acid-substituted and constrained amino acid-substituted cyclo somatostatin analogs that functioned as potent mu opioid receptor antagonists.
All patents and publications mentioned herein are hereby incorporated by reference in their entirety.